5 Insulin Secretion And Intermediary Metabolism

Question 1

Q: What 4 hormones cause glucose levels to rise?

Answer 1

A: glucagon
catecholamine
somatotrophin (growth hormone)
cortisol

Question 2

Q: When comparing high and low blood glucose, what can our body manage for a period of time? What does the alternative cause?

Answer 2

A: high

other is life threatening as brain needs glucose to function (therefore body needs methods of maintaining plasma glucose levels)

Question 3

Q: What is type 1 diabetes mellitus defined as?

Answer 3

A: elated glucose where insulin is required to prevent ketoacidosis

not enough insulin is produced

Question 4

Q: What is ketoacidosis? Can cause?

Answer 4

A: ketoacidosis, the body fails to adequately regulate ketone production causing such a severe accumulation of keto acids that the pH of the blood is substantially decreased

can cause damage to big blood vessels in brain/heart (causing stroke/heart attack)

Question 5

Q: What is type 2 diabetes mellitus defined in terms of?

Answer 5

A: glucose but also related to hypertension and dyslipidaemia

hyperglycaemia

Question 6

Q: Put in order of prevalence; T1DM, T2DM, MODY.

Answer 6

A: T2DM (85%)
T1DM (11%)
MODY (4%)

Question 7

Q: What is the role of diet in treating DM T1 and 2?

Answer 7

A: 1- counting carbohydrates is essential in controlling sugar levels
2- suggested that sufferers have a healthy diet (control calories and fats and refined sugars)

Question 8

Q: As part of DM treatment insulin can be given and its attempted to do so physiologically. Why is this hard?

Answer 8

A: recreating what occurs in a patient is difficult

w/o diabetes, the body makes insulin on a moment to moment basis depending on food intake, aa, glucose

Question 9

Q: Describe glucose monitoring. (3)

Answer 9

A: in the past- measured urine glucose
capillary glucose measuring needs to be done frequently

some patients measure interstitial space glucose (not same as blood glucose) with permanent/semi indwelling monitors

Question 10

Q: The imbalance of what causes hypoglycaemia? (3)

Answer 10

A: diet, exercise, insulin

Question 11

Q: When is hypoglycaemia inevitable?

Answer 11

A: if you have T1DM (low blood sugar)

Question 12

Q: Name 4 complications of diabetes mellitus.

Answer 12

A: Diabetic retinopathy

Nephropathy

Heart attacks

Stroke

Question 13

Q: Why is glucose so important?

Answer 13

A: Glucose is a very important energy substrate, particularly for the CNS which mainly respires glucose under normal conditions- can use ketones (not fats at all)

Question 14

Q: What occurs if blood glucose falls below 4.0-5.5mM?

Answer 14

A: hypoglycaemia- then brain function is increasingly impaired

Question 15

Q: What occurs if blood glucose falls below 2mM? What do most people have?

Answer 15

A: it could lead to unconsciousness, coma and death

have a counter regulatory system that deals w/ low blood sugar (eg alpha cells and glucagon)

Question 16

Q: What is 98% of the pancreas associated with? And the remaining 2%?

Answer 16

A: exocrine secretions via a duct to the small intestine (involved in digestion)

are islets of Langerhans (small clumps of cells within pancreatic tissue)- endocrine secretions (hormone straight into blood stream)

Question 17

Q: What is the structure of the islets of Langerhans? Include diagram.

Answer 17

A: made of 3 cell types; alpha (make glucagon), beta (make insulin), delta

have gap junctions- allow small molecules to pass directly between cells

have tight junctions- form small intercellular spaces between them= have high hormone concentration

Question 18

Q: What do the cell types of the islets of Langerhans produce? (3) What do these molecules do?

Answer 18

A: Alpha= Glucagon= increases blood glucose

Beta= Insulin= stimulates growth and development and decreases blood glucose

Delta= Somatostatin= important in hormone balance since it decreases production of insulin and glucagon

Question 19

Q: What factors affect beta cells and their insulin production? Increase? (4) Decrease? (2)

Answer 19

A: increase

increased blood glucose (MAIN)
certain aa
certain gastrointestinal hormones
parasympathetic activity

decrease

somatostatin from delta cells
sympathetic activity (alpha receptors)- needs stimulus

Question 20

Q: What does increased insulin do? (3)

Answer 20

A: decrease lipolysis +
increase lipgenesis (fat storage)

increase aa transport +
increase protein synthesis

increase gluconeogenesis +
increase glycolysis +
increase glucose transport into cells via GLUT4 -> decease blood glucose

Question 21

Q: What is the neurological control of beta cells? (2)

Answer 21

A: Sympathetic Stimulation - switches off insulin to increase blood glucose concentration

Parasympathetic Stimulation - increases insulin secretion

Question 22

Q: What factors affect alpha cells and their glucagon production? Increase? (5) Decrease? (2)

Answer 22

A: increase

decreased blood glucose (MAIN)
certain aa
certain gastrointestinal hormones
sympathetic activity
parasympathetic activity

decrease

insulin from beta cells
somatostatin from delta cells

Question 23

Q: What does increased glucagon do? (3) Overall.

Answer 23

A: increase lipolysis-> increased gluconeogenesis

increase hepatic glycogenolysis

increase aa transport into liver -> increased gluconeogenesis

all 3 -> increased blood glucose

Question 24

Q: How does low blood glucose treatment giving differ from home and hospital?

Answer 24

A: home- injection of glucagon (if they’re asleep)

hospital- if unconscious -> intravenous glucose

Question 25

Q: What is glucokinase, how does it work (3) and why is it important? Known as? (2)

Answer 25

A: Glucokinase is the Rate Determining Step that regulates insulin secretion

known as glucose sensor and hexokinase IV

1. Glucose enters the beta islet cell via Glucose Transporter 2 (Glut 2) which is not insulin sensitive (NOT INSULIN REGULATED)
2. Glucose is converted to Glucose-6-phosphate by glucokinase which is important for the sensing of glucose concentration by the beta cell
3. metabolic pathways -> insulin synthesis and release

Question 26

Q: What is the structure of insulin? How is it formed?

Answer 26

A: Insulin is constructed as pre-proinsulin which has three chains forming one long chain along with a signal sequence

The C peptide is then removed

Insulin being released by the pancreas is always released with C peptide

The molar ratio of insulin to C peptide is 1:1 so by measuring C peptide you can measure endogenous insulin production and see if the beta cells are functioning

Question 27

Q: Why is insulin given as an injection rather than orally?

Answer 27

A: would be broken down and made inactive if taken orally

Question 28

Q: Illustrate the production of insulin by beta cells. (5)

Answer 28

A: Glucose enters through Glut 2

converted to glucose 6 phosphate -> makes ATP

The ATP produced blocks the ATP sensitive potassium channels

This leads to the opening of voltage dependent calcium channels (membrane potential has changed)

Calcium rushes into the beta cell and stored insulin is secreted and new insulin made

Question 29

Q: What could mean that those with T2 diabetes can make enough insulin?

Answer 29

A: if glucose exposure was prolonged (since they can’t produce enough insulin at once to deal with the meal)

Question 30

Q: What is the incretin effect? Include experiment.

Answer 30

A: When we eat a meal and there is food in our intestine we start producing insulin

In this experiment someone is given a 50g oral glucose load and a matched intravenous infusion of glucose to cause exactly the same glucose profile

When given oral glucose, he makes considerably more insulin - this is the incretin effect

Incretin Effect - food stimulates more insulin secretion if given orally rather than intravenously

Question 31

Q: Describe glucagon like peptide-1 (GLP-1). What is it? When is it secreted? How? What does it stimulate and affect? (3) Half life?

Answer 31

A: Gut hormone

Secreted in response to nutrients in the gut

It is a transcription product of the proglucagon gene - mostly from the L cell

Stimulates insulin and suppresses glucagon

Increases satiety (increases feeling of fullness)

They have a short half life due to rapid degradation by the enzyme Dipeptidyl Peptidase-4 (DPPG-4)

Question 32

Q: Illustrate first phase insulin release on a diagram. 2 lines. Why is it important? Get around by?

Answer 32

A: 1. The normal person has an intravenous glucose load which makes him produce a lot of insulin instantly

2. The person with T2DM has next to no first phase insulin - the insulin is made later on (no insulin store available)
   If someone has an oral glucose load you don’t see the first phase because it’s over 30 mins

First phase insulin release is important is important in switching off liver glucose production

can get round physiological process by prolonging calorie exposure- give patients meals that give calories over 2/3 hours and not a high glucose meal

Question 33

Q: Illustrate the insulin receptor. (4)

Answer 33

A: 2 alpha subunits= extracellular domains (insulin above)

membrane
beta subunits with tyrosine kinase domains

^ (autophosphorylation and cross-phosphorylation of receptors)

-phosphorylation of cell protein substrates

Question 34

Q: How do abnormalities in the insulin receptor cause T1 and 2 DM?

Answer 34

A: they don’t

Insulin resistance lies in the post receptor cytoplasmic elements of insulin function

Question 35

Q: What occurs when insulin binds to its receptor? (2) Effects? (4) What’s important and why?

Answer 35

A: The alpha subunit of the insulin receptor recognises the 3D shape of insulin

which causes a conformational change in the beta subunits which cross the membrane

• this has a metabolic effect on glucose,
• amino acids
• and fatty acids
• It also affect growth (mitogenic pathway)

Phosphorylation of beta subunits is important in recruiting substrates which go on to have effects on the metabolic pathway